|
KMID : 0617219990100010053
|
|
Duksung Bulletin Phamaceutical Sciences
1999 Volume.10 No. 1 p.53 ~ p.56
|
|
|
CYP3A4-Mediated Oxidation of Lisofylline to Lisofylline 4,5-Diol in Human Liver Microsomes
|
|
SHIN HEA-SOON
JOHN T SLATTERY
|
|
|
Abstract
|
|
|
|
The cytochrome P450s responsible for the conversion of lisofylline, a drug being developed to prevent the complications of high-dose chemotherapy, to lisofylline 4,5-diol, one of two principal metabolites in human liver microsomes, were evaluated. Lisofylline diol formation in microsomes prepared from five adult human livers was biphasic, with respective K_m values of 0.0230±0.015 and 4.23±2.8 mM(mean ± SD) and respective V_max values of 0.0565±0.052 and 0.429±0.15 nmol/min/mg of protein. Through studies with isoform selective chemical inhibitors, CYP3A4 was implicated as the low K_m enzyme from 89.0±11.2％ inhibition of lisofylline 4,5-diol formation by troleandomycin at 50 uM substrate and CYP2A6 was implicated as the high K_m enzyme. The formation of lisofylline 4,5-diol by these enzymes was confirmed with cDNA-expressed human CYP3A4 and CYP2A6.
|
|
|
KEYWORD
|
|
|
|
|
|
FullTexts / Linksout information
|
|
|
|
|
|
Listed journal information
|
|
|
|
|